{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe actin‐bundling protein PLS3 has emerged as a key disease modifier in spinal muscular atrophy (SMA), where its elevated expression can protect motor neurons and extend survival when combined with SMN‐inducing antisense oligonucleotide therapies. These studies indicate that augmenting PLS3 levels helps counteract the detrimental effects arising from SMN1 loss by supporting neuromuscular function and complementing SMN restoration strategies, thereby broadening the therapeutic approach for SMA."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of skeletal physiology, balanced PLS3 expression is crucial for proper bone remodeling. Elevated PLS3 levels can enhance cortical bone strength by modulating osteoclast development and function through its influence on the NFκB–NFATC1 axis, in part by promoting the nuclear translocation of inhibitory factors such as NKRF. Conversely, loss‐of‐function mutations or deficiency in PLS3 disrupt intracellular calcium regulation via impaired interactions with binding partners like LCP1, ultimately leading to osteoporosis and cortical thinning."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in neuromuscular and bone homeostasis, PLS3 is essential for cytoskeletal organization and tissue morphogenesis. It regulates epithelial polarity and basement membrane assembly by coordinating the cortical actomyosin network and ensuring proper localization and activation of myosin II. Moreover, specific missense variants within PLS3’s actin‐binding domains—rather than causing loss of function—may exert a gain‐of‐function effect that disrupts normal developmental processes, as exemplified by congenital diaphragmatic hernia and associated anterior body‐wall defects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kevin A Kaifer, Eric Villalón, Erkan Y Osman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "JCI Insight (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/jci.insight.89970"}], "href": "https://doi.org/10.1172/jci.insight.89970"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28289706"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28289706"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Eike A Strathmann, Miriam Peters, Seyyedmohsen Hosseinibarkooie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evaluation of potential effects of Plastin 3 overexpression and low-dose SMN-antisense oligonucleotides on putative biomarkers in spinal muscular atrophy mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0203398"}], "href": "https://doi.org/10.1371/journal.pone.0203398"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30188931"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30188931"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "L Wang, Q Zhai, P Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of p.Ala253_Leu254insAsn mutation in PLS3 responsible for X-linked osteoporosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cge.13081"}], "href": "https://doi.org/10.1111/cge.13081"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28646489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28646489"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Janine Neugebauer, Juliane Heilig, Seyyedmohsen Hosseinibarkooie, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Plastin 3 influences bone homeostasis through regulation of osteoclast activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy318"}], "href": "https://doi.org/10.1093/hmg/ddy318"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30204862"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30204862"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Timur Alexander Yorgan, Hatice Sari, Tim Rolvien, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mice lacking plastin-3 display a specific defect of cortical bone acquisition."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Bone (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bone.2019.115062"}], "href": "https://doi.org/10.1016/j.bone.2019.115062"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31678489"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31678489"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Eyal Dor-On, Shaul Raviv, Yonatan Cohen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "T-plastin is essential for basement membrane assembly and epidermal morphogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.aal3154"}], "href": "https://doi.org/10.1126/scisignal.aal3154"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28559444"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28559444"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Florence Petit, Mauro Longoni, Julie Wells, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2023.09.002"}], "href": "https://doi.org/10.1016/j.ajhg.2023.09.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37751738"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37751738"}]}]}]}